Targeting triple negative BREAst cancer metabolism with a combination of chemotherapy and a diet mimicking FASTing plus/minus metformin in the preoperative setting: the BREAKFAST trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione IRCCS Istituto Nazionale Dei Tumori, Fondazione IRCCS Istituto Nazionale Dei Tumori

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

20 May 2020 → ongoing

Decision date (initial)

2023-11-21

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2023-508920-37-00

EudraCT number

2019-003093-13

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

To investigate if the experimental treatments, consisting in the combination of triweekly anthracycline-taxane chemotherapy with cyclic FMD, with or without daily metformin, are able to increase the rate of pCR when compared to historical results with standard anthracycline-taxane chemotherapy.

Secondary objectives 11

1. To assess the tolerability of the experimental arms, and in particular to evaluate the occurrence of severe (grade 3/4) adverse events (AEs)
2. To evaluate the safety of each experimental treatment, and in particular to evaluate treatment-related AEs
3. To study patient compliance, as defined as the ability to adhere to the prescribed FMD regimen and pharmacological treatment (i.e. metformin) based on the analysis of food and drug diaries
4. To estimate clinical tumor responses, as assessed through Contrast-enhanced mammography (CESM) and contrast-enhanced magnetic resonance imaging (CE-MRI) evaluations according to RECIST 1.1 criteria before surgery
5. To estimate patient relapse-free survival (RFS) in both experimental arms
6. To evaluate distant metastasis-free survival (DMFS) in both experimental arms
7. To evaluate Overall Survival (OS) in both experimental arms
8. To study the short-term (intra-cycle) and long-term (across subsequent cycles) effects of the experimental treatments on systemic metabolism by evaluating several blood metabolites, including plasma glucose, insulin, insulin-like growth factor 1 (IGF-1) levels and whole blood and plasma lipid profile
9. To correlate experimental treatment-induced modifications of systemic metabolism and immunity with treatment activity, in terms of pCR, RFS, DMFS and OS
10. To correlate tumor gene expression profiles with the efficacy of the experimental arms, defined on the basis of rates of pCRs 19.
11. To correlate the tumor mutational status of genes involved in DNA repair, and in the mechanistic Target Of Rapamycin Complex 1 (mTORC 1), PP2A, autophagy and Beclin 1 pathways with the efficacy of the experimental treatments, defined as the rate of pCRs.

Conditions and MedDRA coding

Triple negative breast cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Female sex
2. Age ≥ 18 and ≤ 75 years.
3. Evidence of a personally signed and dated informed consent document (ICD) indicating that the patient has been informed of all pertinent aspects of the study before enrollment
4. Willingness and ability to comply with the prescribed FMD regimen, metformin intake, the scheduled visits, treatment plans, laboratory tests and other procedures
5. Histologically confirmed diagnosis of invasive TNBC candidate to neoadjuvant chemotherapy and subsequent curative surgery. On the basis of International Guidelines, TNBC is defined by absent or minimal (<1%) expression of oestrogen and progesterone receptors at IHC, and absence of HER2 over-expression or amplification, as defined as an IHC score of 0, 1+, or an IHC score of 2+ with in situ hybridization (ISH) analysis excluding HER2 gene amplification
6. Patients with localized disease (clinical stage I-III according to TNM). Patients with Stage I TNBC will be included only if the primary tumor is at least 10 mm in greatest dimension (clinical T1c as determined through baseline CESM and CE-MRI assessment).
7. Presence of an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
8. Presence of adequate bone marrow and organ function as defined by the following laboratory values: a. ANC ≥ 1.5 x 10^3/lb. platelets ≥ 100 x 10^3/l c. hemoglobin ≥ 9.0 g/dl d. calcium (corrected for serum albumin) within normal limits or ≤ grade 1 according to NCI-CTCAE version 5.0 if not clinically significant e. potassium within the normal limits, or corrected with supplements f. creatinine < 1.5 ULN g. blood uric acid < 10 mg/dl h. ALT and AST ≤ 2 x ULN i. total bilirubin < 1.5 ULN except for patients with Gilbert syndrome who may only be included if the total bilirubin is < 3.0 x ULN or direct bilirubin < 1.5 x ULN j. Fasting glucose ≤ 250 mg/dl.
9. Female patients of childbearing potential must agree to sexual abstinence or to use two highly effective methods of contraception throughout the study and for at least six months after the end of the FMD. Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the patient. Examples of contraceptive methods with a failure rate of < 1% per year include tubal ligation, male sterilization, hormonal implants, established, proper use of combined oral or injected hormonal contraceptives, and certain intrauterine devices. Alternatively, two methods (e.g., two barrier methods such as a condom and a cervical cap) may be combined to achieve a failure rate of < 1% per year. Barrier methods must always be supplemented with the use of a spermicide. A patient is of childbearing potential if, in the opinion of the Investigator, she is biologically capable of having children and is sexually active.
10. Female patients are not of childbearing potential if they meet at least one of the following criteria: a. Have undergone a documented hysterectomy and/or bilateral oophorectomy b. Have medically confirmed ovarian failure c. Achieved post-menopausal status, defined as: ≥ 12 months of non-therapy-induced amenorrhea or surgically sterile (absence of ovaries) and have a serum FSH level within the laboratory’s reference range for postmenopausal females.

Exclusion criteria 21

1. Prior systemic treatment for breast cancer or other malignancies within 5 years of treatment enrollment.
2. Prior treatment with anthracyclines
3. Diagnosis of other malignancies in advanced stages (unresectable, locally advanced or metastatic), or that required systemic (neo)adjuvant chemotherapy in the previous 5 years. Other malignancies diagnosed more than 5 years before the diagnosis of breast cancer must have been radically treated without evidence of relapse at the moment of patient enrollment in the trial
4. Body mass index (BMI) < 20 kg/m^2.
5. History of alcohol abuse.
6. Non-intentional weight loss ≥ 5% in the previous 3 months, unless the patient has a BMI > 22 kg/m^2 and weight loss has been lower than 10% at the time of enrollment in the study; or non-intentional weight loss of ≥ 10% in the previous 3 months, unless the patients has a BMI > 25 kg/m^2 and weight loss has been lower than 15% at the time of the enrollment in the study. In both cases, weight must have been stable for at least one month before study enrollment
7. Active pregnancy or breast feeding.
8. Known active B or C hepatitis or human immunodeficiency virus (HIV) infection, or occasional finding of active hepatitis B/C infection during screening tests before chemotherapy initiation, as defined as positive polymerase chain reaction (PCR) testing for HBV-DNA and HCV-RNA and qualitative PCR for HIV-RNA, or requiring active treatment at study enrollment.
9. Serious infections in the previous 4 weeks before the FMD initiation, including, but not limited to, potential hospitalizations for complications of infections, bacteriemia or serious pneumonitis.
10. Active autoimmune diseases requiring systemic treatments (e.g. systemic steroids or immune suppressants).
11. Active chronic therapy with systemic steroids at a dose ≥ 10 mg per day of prednisone or equivalent at study enrollment
12. Known recent diagnosis of hypothyroidism requiring systemic replacement hormonal therapy and without stabilization of hormonal profile (fT3, fT4 and TSH within the normal range).
13. Diagnosis of type 1 or 2 diabetes mellitus requiring pharmacologic therapy (including, but not limited to, insulin, secretagogues and metformin). A diagnosis of type 2 diabetes mellitus not requiring pharmacological treatments based on the judgment of a diabetologist, is compatible with patient enrollment in the trial.
14. Active gastric or intestinal ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small intestine resection.
15. Anamnesis of clinically significant heart disease including: a. angina pectoris, coronary bypass, symptomatic pericarditis, myocardial infarction in the previous 12 months from the beginning of experimental therapy; b. congestive heart failure (NYHA III-IV).
16. Anamnesis of clinically meaningful cardiac arrhythmias, such as ventricular tachycardia, chronic atrial fibrillation, complete bundle branch block, high grade atrio-ventricular block like bi-fascicular block, type II Mobitz and third grade atrio-ventricular block, nodal arrhythmias, supra-ventricular arrhythmia.
17. Left ventricular ejection fraction lower than 50% at the cardiac scan with radionuclides or at echocardiography.
18. Previous episodes of symptomatic hypotension leading to loss of consciousness.
19. Baseline plasma fasting glucose ≤ 60 mg/dL.
20. Medical or psychiatric comorbidities rendering the patient not candidate to the clinical trial, according to the investigator’s judgement.
21. Other cardiac, liver, lung or renal comorbidities, not specified in the previous inclusion or exclusion criteria, but potentially exposing the patient to a high risk of lactic acidosis.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Pathologic complete response (pCR), as defined as the absence of residual tumor cells in both breast tissue and axillary lymph nodes.

Secondary endpoints 13

1. Relapse free survival (RFS), as defined as the time from surgery to tumor recurrence, either local or distant
2. Distant metastasis free survival (DMFS), as defined as the time from surgery to the occurrence of distant metastases
3. Overall Survival (OS), as defined as the time from randomization to the date of death. Patients alive at time of data cut-off and analysis will be censored at their last contact date
4. Metabolic biomarkers (e.g. plasma glucose, insulin, insulin-like growth factor 1 (IGF-1) levels and whole blood and plasma lipid profile, fecal microbiota) assessed at baseline and at each chemotherapy cycle
5. Role of DNA repair, mTORC 1, PP2A, autophagy and Beclin 1 pathways in the efficacy of the experimental treatments, defined as the rate of pCRs
6. Dose-intensity, that is the dose of effective drug administrated per unit of time (e.g. mg/m2/week)
7. Percentage of patients with drug dose and/or time modifications
8. Percentage of patients with experimental dietary regimen modifications
9. Percentage of premature withdrawals
10. Incidence, nature, severity and seriousness of AEs, according of NCI-CTCAE, version 5.0
11. Maximum toxicity grade experienced by each patient for each specific toxicity
12. Percentage of patients experiencing grade 3-4 toxicity for each specific toxicity
13. Patients with at least a SAE

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione IRCCS Istituto Nazionale Dei Tumori

Sponsor organisation

Fondazione IRCCS Istituto Nazionale Dei Tumori

Address

Via Giacomo Venezian 1

City

Milan

Postcode

20133

Country

Italy

Scientific contact point

Organisation

Fondazione IRCCS Istituto Nazionale Dei Tumori

Contact name

Clinical Trials Center

Public contact point

Organisation

Fondazione IRCCS Istituto Nazionale Dei Tumori

Contact name

Clinical Trials Center

Fondazione IRCCS Istituto Nazionale Dei Tumori

Sponsor organisation

Fondazione IRCCS Istituto Nazionale Dei Tumori

Address

Via Giacomo Venezian 1

City

Milan

Postcode

20133

Country

Italy

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Application history

1 submissions — initial application plus substantial / non-substantial modifications